Diamine oxyalkyl compounds



United States Patent 3,352,917 DIAMINE OXYALKYL COMPOUNDS John C. James,Melrose, Robert J. Wineman, Concord, and Morton H. Gollis, Brookline,Mass., assiguors t0 Monsanto Research Corporation, St. Louis, Mo., acorporation of Delaware No Drawing. Original application Nov. 25, 1964,Ser. No. 413,953. Divided and this application May 19, 1966, Ser. No.600,278

2 Claims. (Cl. 260-584) This is a division of application Ser. No.413,953, filed Nov. 25, 1964, which is a continuation-in-part ofapplication Ser. No, 176,409, filed Feb. 28, 1962.

This invention relates to new chemical compounds, and more particularly,provides novel mercaptoalkyl oxyalkyl amines.

Aliphatic mercaptoalkyl oxyalkyl amines in which at least one of theamino N and my 0 atoms is exocyclic have not been knOWn heretofore.Where these atoms are exocyclic, they can exert effects such asmodifying the polarity, basicity and hydrophilicity of the compoundswhich are not observed when they form part of the same ring, and onlythe mercaptoalkyl group is exocyclic. Also, one or both or the amino Nand oxy O atoms may carry hydrogen as a substituent, and thereby besusceptible of activity such as hydrogen bonding in a biological system,chemical reactivity and the like. These factors may produce protectiveeffects in biological systems at sublethal levels.

It is an object of this invention to provide novel com pounds.

A particular object of this invention is to provide novel mercaptoalkyloxyalkyl amines in which at least one of the amino N and oxy O atoms isexocyclic.

Another object is to provide a novel method of protecting biologicalorganisms from harmful conditions.

These and other objects will become evident from a consideration of thefollowing specification and claims.

The compounds provided by this invention are N-mercaptoalkyl oxyalkylamines in which at least one of the amino N and oxy O atoms isexocyclic; and alkanoate esters and acid addition salts thereof.

It has been found that administration of compounds of the stated type asdescribed hereinafter protects biological organisms from the harmfuleffects of ionizing radiation.

The amines of this invention, by which is meant the said mercaptoalkylamines as distinguished from their esters and acid addition salts, maybe described as N- mercaptoalkyl oxyalkyl amines containing from 1 to 2amino nitrogen atoms, and from 1 to 3 oxyalkyl radicals and from 1 to 2mercaptoalkyl radicals attached to said nitrogen atoms, at least one ofsaid oxy oxygen and said amino nitrogen atoms being exocyclic.

The invention includes a number of different types of mercaptoalkyloxyalkyl amines, a comprehension of which will be facilitated byconsideration of the specific classes included herein as follows.

A first class of compounds provided hereby are monoamines of the formulacarbon and x is an integer of from 1 to 3.

By each R is meant R and R and by each R, R and R and so forth.

If R is H, these are alcohols. Embodiments of the invention includesecondary amino and tertiary amino 3,352,917 Patented Nov. 14, 1967mono-alkanols and polyalkanols as pointed out hereinafter, such as If Ris hydrocarbon, the embodimentof the invention is an ether, such asWhere x is 2 or 3, the R groups may be different, one being H and onealiphatic hydrocarbon, representing the embodiment of the inventioncomprising alkoxy alkanols, such as or each R may be the same, providingembodiments of the invention such as polyols like An embodiment of theinvention included in the abovestated groups comprises alicycliccompounds, such as A further embodiment of this invention comprisesheterocyclic alcohols and ethers, Where two of the radicals symbolizedby R R and R are aliphatic hydrocarbon forming part of the same chain.These alcohols and ethers may be azacyclic, such as A second class ofamines provided by this invention comprises diamines.

In a first embodiment of this class, the said diamines arealkylenediamines in which one of the amine nitrogen atoms is attached toa mercaptoalkyl radical, one of the nitrogen atoms is attached to anoxyalkyl radical, and all the other nitrogen substituents of thediamines are selected from H and saturated aliphatic hydrocarbons. Theseare represented by the formulas:

and

Where each R is saturated aliphatic hydrocarbon,

each R is selected from the class consisting of hydrogen and saturatedaliphatic hydrocarbon,

and x is an integer of from 1 to 3.

Like the above mono-amines, this class of diamines includes alcohols andothers. Illustrative of such alcohols are the diamines of the aboveformula which are mercaptoalkylamino oxyalkylamines, with the oxyalkylradical attached to both nitrogens, such as The embodiment of thesediamines where the oxyalkyl radical is attached to one nitrogen and themercaptoalkyl to the other may be illustrated by an ether such as In asecondembodiment of the class of diamines of this invention, thediamines are bis-N-mercaptoalkyl oxyalkane-diamines. ,They arerepresented by the general formula HSR1N- 112( 2) 2 r Rt '2' where eachR is saturated aliphatic hydrocarbon, each R is selected from H andsaturated aliphatic hydrocarbon, andx is an integer of from 1 to 3.

These diamines are illustrated, for example, by a member of the groupcomprising alkanediols of the stated type, such as- HS-CHaGHz-NH-CHzCHOHHS-CHzCHz-NH-CHr-CHOH From the foregoing it will be. evident that thepresent amines can be generally described as mercaptoalkyl oxyalkylmonoand di arnines in which at least one of the oxy O and amino N atomsis exocyclic, and in which all the nitrogen substituents are selectedfrom the class consisting of H, saturated aliphatic hydrocarbon;oxyalkyl and mercaptoalkyl radicals; Oxy designates connective oxygen,joining C to H or forming the sole bond between two C atoms; thepresently provided amines are completely saturated, and free of C-O andCN unsaturation as-well as ofcarbon-to-carbon unsaturation. Furthercharacterizing the amines of this invention is the fact that thenitrogen atoms thereof are at leasttwo-carbon atoms removed from heteroatoms (atoms other than C, including 0 and S). The 2-mercaptoalkyl and3'-mercaptoalkyl amines are preferred, and the compounds in which thenitrogen atom is beta to each of 'a sulfur-substituted carbon atom andan oxygen-substituted carbon atom are especially preferred. Aparticularly preferred class of the present amines comprises thecompounds in which at least one of the ,O and N atomsis hydrogensubstituted;

As noted above, this invention also provides esters of the statedamines. This includes esters of one or both of the mercaptan functionand of the hydroxy function, where it is present in these amines. Theesters included are those of these amines with alkanoic acids, that is,acids consisting of a saturatedaliphatic hydrocarbon radical attachedto: the carboxylic'funct-ion,

Eachof the saturated aliphatic hydrocarbon radicals of the amines andtheir esters. of this invention ishydrocarbon of uptol'8lcarbon'atorns;v

The acid addition salts of the compounds of this invention includesaltsofithe stated amines andof their esters. The acid used to formthese salts may be inorganic or organic protonic acids, of the usualtype employed in the art to form amine salts, such as hydrochloric andhydrobromic, for example. Physiologicall-y acceptable salts of theamineswith, non-toxic acids, suchas the hydrochlorides, are preferred;The presently provided compounds are usefulas, pharmaceuticals; they areantiradiation drugs which protect animals against thelethal and toxiceffects of ionizing radiation.

The scopeof the present invention'will be best appreciated from aconsideration at this point of the following examples,v which areillustrative but not limiting. In these examples,- all parts are byweightunless otherwisenoted.

EXAMPLE 1 This example illustrates the compounds provided by thisinvention; by a tabular list offormulas, methods of preparation (Prep)and characterizingrproperties of such,

compounds. In the tables, methodsof preparation are indicated as' A, Bor C. Briefly, method A is reaction of anoxyalkylamine with ethylenesulfide; method B is reac- 7 Prep. Properties HS-(CHz)2--NH-C H-C HCHZCHEC HgCHg B HCl m. loo-103 (dec.)

Hs(0H.) -N-0H.-0H,0H 0 H01 hyg. 611.

HS(CHz) --NCH -CH;OH C HCI an oil.

Hs-(0H,).N-0H.-0H.0H A b. 71/0.5 mm., m 1.4966; HCl an 611, nD 1.5265.

G HaC Ha HS-(C H.)1N0 H.0 H. 0 H 0 H01 111. 74-76".

HS'(C H2)2-N-CH2-OH2OH 0 H01 an oil.

CHzCHgCHgCH;

HS-(CH2)2NOHiOHCH CH CH; A H01 111. 125.

HS-(C Hz)2NH-C H.-0 H20 0H. A b. 84l17 mm, n 1.4767; H01 111. 93-107".Hs-(0 H.).NH-0 H.-0 11.0 H10 0 H3 A b. 80/4 mm., 11. 1.4600,- H01 in.5866. HS-(CHz)2NH-C H2 C HgCHzO CH(CHa)2 A b. 74/0.8 mm., nun 1.4679;H01 In. 961()8. HS(CH2)z NH-CH1-CH2OH2O CH(CHI)GCHQ A b. 13S140/0.1 mm.,mm 1.4668.

$4Hu-n HS(CH2)2-NH-C Hr-(EH-O-CHzCHzCH CfiH; A b. 7980/0.3 mm., n1.5040; HO! m. 155170 (11%.);

Hs-(C H:)2-NH-C H2-0 H0 H7O H 0 H01 an 011.

HS-(CHzh-NH-C'Hr-CHOH B ZHCI m. 227-229 (1160.). HS-(O H2)2-NH-C Hr-O110 H Hs(0H.).NH-0(0H.0H)6 0 1101.... 110112 0.

HS-(C H.).-NH-0 H.-o Homo on. B H01 hyg. oil.

HS-(G Hm-NH-U H.0 H0 1110(0 H930 H; B H01 hyg. 011.

HS-(C Hzh-NH-C Ha-C H0 H20 (0 H940 Ha B 1101 an 011.

B s-(0 H3)1NHO Iii-0 H0 HzN(C H20 Ha): A b. 98-99", mm 1.4942; 1101 m.191-192.5.

HS(C H2)a-NH-C H.-0 H10 Hu vo HzCHzO 0H H. A b. 119/0.4 mm., mm 1.5086;H01 111. 225-230 (100.).

S-(CHQ -NH-CH -CHCHzCH H01 111. 72-74".

EXAMPLE 2 6O invention, Where the initial amine is too polar to haveThis example illustrates Method A, ring-opening of an alkylene sulfide,employing a non-polar amine.

A solution of 56 parts 3-methoxypropylamine in benzene is refluxed(about 85 C.) while a solution of ethylene sulfide is added graduallyuntil 38 parts of the sulfide has been introduced. The reaction mixtureis cooled and filtered, and solvent is removed from the filtrate byevaporation to leave a residue Which is distilled. The fraction comingover at above column head temperature at from 4.5 down to 0.5 mm. isrecovered: 11 1.4800. This is 2-[( 3-methoxypropyl) amino]ethanethiol.

EXAMPLE 3 This example describes a procedure in the scope of method Afor preparation of one of the amines of this significant solubility inbenzene.

A 10% by volume solution of ethanol and benzene is prepared by combining320 parts by volume of ethanol with 2880 parts by volume of benzene, andthis mixture is dried azeotropically by refluxing. Then 560 parts byWeight of 2-amino-ethanol is added to the solvent mixture and refluxingto dry the reaction mixture is continued. When the system has beensubstantially freed of Water, introduction of ethylene sulfide isinitiated, by dropwise addition of a solution of ethylene sulfide inbenzene until 55 parts by Weight of ethylene sulfide has been added overa period of between 3 and 4 hours. Refluxing is continued after theaddition is complete for an hour and then solvent is removed from thereaction mixture by heating under vacuum. The clear oily residue isdistilled and the fraction boiling at between 66 and 72 C. column headtemperacaptoethyl)amino1-ethanol. It is a solid at room tempera ture,melting at about 55-60 C.

Proceeding similarly, ethylene sulfide is reacted with' 1-amino-3-diethylamino-2-propanol to provide l-diethylamino-3 (Z-mercaptoethylamino] -2-propanol.

EXAMPLE 4 This example describes preparation of the acid addition saltof an amine.

A solution of 37 parts of 2-[(2-mercaptoethyl)amino]- ethanol, preparedas described in Example 3, in 100 parts of water is blanketed withnitrogen, and the solution is stirred while 6 N hydrochloric acid isadded until just sufficient has been introduced to make the solutionacid. Then water is removed and the oily residue dried. The product isthe hydrochloride salt of 2-[(2-mercaptoethyl) amino] ethanol, an oil, n1.5570.

Another useful technique for preparation of the amine salts of thisinvention comprises dissolving the amine in an organic solvent such asethanol and adding acid thereto, employing a non-aqucous system. Forexample, dry hydrogen chloride may be passed as a gas into an ethanolsolution of the amine, until the solution is saturated.

One or the other of the stated methodsis employed to prepare thehydrochloride salts of the amines shown in the above table.

EXAMPLE 5 This example illustrates the formation of a2-[(benzylthio)alkylamino]alkanol in accordance with Method B of theinvention.

A solution of 125 parts of 2-(benzylthio)ethylamine in methanol ismaintained under a blanket of nitrogen and rapidly stirred while it isheld at a temperature of -50 C. and about 40 parts of propylene oxideare introduced. The reaction mixture is held for another half hour atand then solvent is removed by evaporation to leave a colorless oil. Theoil is distilled through a Vigreaux column and the fraction boiling atabout 146 C. column head temperature at 0.05 mm. is recovered. Theproduct is 1-( [2-(benzylthio)ethyl]amino)-2-propanol. The oily amine isconverted to the hydrochloride by dissolving a sample of the, oil inabsolute ethanol, saturating the solution with dry HCl and addinganhydrous ether to precipitate the acid addition salt.

Proceeding similarly, employing the appropriate alkylene oxide and2-benzylthioethylamine or 3-benzylthiopropylamine, the followingbenzylthioalkylamines are prepared.

EXAMPLE 6 This example illustrates preparation of a benzylthioalkylamine in accordance with method C of this invention.

A reaction mixture is prepared by combining 185 parts of benzyl2-chloroethylsulfide and 75 parts of 1-amino-2- propanol in ethanol withabout partsof sodium carbonate. The reaction mixture is refluxed undernitrogen for 18 hours. The solvent is removed, water is added, andconcentrated HCl is then introduced to bring the solution to an acid'pH. The acidic mixture is extracted with ether and the resulting aqueouslayer neutralized with 50% aqueous NaOH to form an oil which isextracted with ether. The extract is dried" over sodium sulfate, theether is removed and the oil distilled. The fraction distilling over at133-135 C./0.l3 mm. column head temperature is dissolved in ethanol, andthe solution is saturated with dry HCl. Addition of ether and chillingprecipitates thehydrochloride salt of 1-([2-(benzylthio)ethyl]-amino)-2-propanol. This hydrochloride salt melts at 107-108 C. A mixed meltingpoint of this hydrochloride salt and the hydrochloride prepared asdescribed in Example 5 is the same, thus corroborating the structureassigned to the product of Example 5. The salts also have identicalinfrared spectra.

Using a substantially similar procedure, reaction of benzyl2-chloroethylsulfide or benzyl 3-chloropropyl sulfide with appropriateamines produces the following oxyalkyl benzylthioalkyl amines:

2-( [3- (benzylthio propyl] amino )etlianol', B'. 149-151 0.101nrn., 111.5635, .1 1.091

1-( [3 (benzylthio propyl'] amino -2-propanol-, n

2-( [2'- (benzylthio )ethyl] m'ethyl'amino) ethanol,

2-( [3 (benzylthio propyl] methylamino )ethanol, B.

131 /0.055 mm., 11 1.5506,'d 1.060

2-( [2- (benzylthio )ethylilisopropylamin'o )eth'anol, B.

2-( [2-( benzylthio) ethyl] -n-butylamino) ethanol,

3 [2- (benzylthio ethyl] amino -1 ,2'-propanediol, B.

180-490 /O.1 mm. 11 1.5710

2-( [2- (benzylthio )ethyl] amino) -2-hydroxymethyl-1,3-

propanediol hydro chloride, M. 108-110 EXAMPLE 7 This exampleillustrates conversion ofa benzylthiowith Methods B and Cof thisinvention.

Enough sodium is added to anhydrous liquid ammonia to produce thecharacteristic blue color of sodium in liquid ammonia and then 45 partsof 1-(EZ-Gbenzylthiokthyl] amino)-2-butanol is mixed with the ammoniaand 9 parts of sodium are added, portion-wise, to the ammonia over aperiod of about an hour. Addition of the last of the sodiumafter thelast of the amine causes its blue color to persist, showing completionof thereaction. Ammonia is now removed by evaporation leaving a residueof finely divided powder. The residue is stirred in an ice bath while itis acidified with aqueous HCl. An oily layer is separated and discarded,the acidic mixture is extracted with ether, and the ether extracts arediscarded. The aqueous layer is then filtered, and evaporated down. Theresidue from this procedure is extracted with isopropanol and theextract concentrated to give a white waxy solid, very soluble inalcohols ranging from methanol to butanol and in acetonitrile. The solidis dissolved in-isopropanol andfiltered to free it of the inorganic salt(ammonium and sodium chlorides), and then the solvent is removed toisolate the hydrochloride salt of 1-[ (Z-mercaptoethyl) amino']butanolas'a waxy white solid, M. 83-91" C.

Calc. for C H ClNOS: C, 38.80; H, 8.69; C1, 1909; N, 7.54; S, 17.27.Found: C, 39.1; H, 8.6; Cl, 18.8; N, 7.8; S, 17.1.

Proceeding similarly, the benzylthioalkylamines ment'ioned above inExamples 5 and .6 are debenzylated' to provide the correspondingmereaptoalkylamines.

This example describes preparation of an ester in accordance with theinvention.

Addition of 24 parts of acetyl chloride to 6 parts of1-[(S-mercaptopropyl)amino]-2 butanol hydrochloride, providing a :1molar ratio produces spontaneous reflux of the mixture accompanied byvigorous evolution of hydrogen chloride. The resulting solution ismaintained at reflux for 2 /2 hours, after which excess acetyl chlorideis removed. Trituration of the oily residue with anhydrous etherproduces the diacetate of l-[(3-mercaptopropyl) aminoJ-Z-butanolhydrochloride as a white solid having an infrared spectrum exhibitingtwo strong carbonyl bands, one attributed to the oxygen ester at 5.7aand the other to the thio ester at 5 .9,u.

Proceeding similarly, addition of acetyl chloride to 2 [(2methoxyet-hyl)amino]ethanethiol produces the mono-acetate thereof.

To provide the mono-propionate of 2-[(2-mercaptoethyl)-arnino]ethanol,ethanolamine hydrochloride is esterified with propionic anhydride toprovide 2-aminoethanol propionate hydrochloride, this is neutralizedwith base to provide the free amine, and the resulting product is thenmercaptoethylated with ethylene sulfide in a mixed solvent systemfollowing the procedure of Example 3.

Generally similar procedures provide the mono and diesters of others ofthe presently provided amines.

EXAMPLE 9 This example illustrates use of amines provided by thisinvention.

The hydrochloride salt of 1-[(Z-mercaptoethyl)amino]- 2-propanol isdissolved in water to provide a physiologically acceptable solutionhaving a pH between 7 and 7.5, at a concentration of 3%. The solution isinjected subcutaneously into mice, at a level of 300 mg./kg. body weight(calculated on free amine), which level has previously been determinedto be well below a lethal dosage. Fifteen minutes after the injection,the injected animals are exposed to X-ray radiation, along with othermice which have received an injection of neutralized aqueous HCl, as acontrol. The test animals are then held in cages and fed and wateredwhile they are observed. At a radiation level of 600 roentgens, 55% ofthe controls are dead in from 12 to 19 days; at 825 roentgens, all thecontrols are dead in Within 2 Weeks. All of the animals receiving thedrug injection before exposure to the radiation, however, are alive atthe end of the full 30 day test period.

Good protective results are similarly produced using a r 350-500 mg/kg.dosage of the hydrochloride salts of 2-[ Z-mercaptoethyl amino]ethanol,3-[(2-mercaptoethyl) amino]-1,2-propanediol,1-[(2-mercaptoethyl)ammo]-3-methoxy-2-propanol, and l,4-bis[2-mercaptoethyl) amino]-2,3 -butanediol.

Referring now to the scope of this invention, the monoamines providedhereby include mono-oxy and poly-oxy compounds composing the sub-classesof alcohols, ethers and alkoxyalkanols.

The alcohols which are monohydric and acyclic are illustrated bymono-amines including secondary amines such as 2-[ Z-mercaptoethyl)amino] ethanol,

2[ (Z-mercaptopropyl) amino]ethanol,

2-[ Z-mercaptoethyl) amino} l-prop anol,

3 Z-mercaptoethyl amino]- 1 -propanol, 3-[ Z-mercaptoethyl)amino]-n-butanol, 2-[(2-mercaptoethyl) amino]- 1 -butanol, 3-[Z-mercaptoethyl arnino]-2-propanol, 1-[ 3 -mercaptopropyl)amino]-2-propanol, 1-[(2-mercaptodecyl)amino1-2-butanol, 1-[ 3-mercaptopropyl) aminol-Z-butanol,

1-[ (Z-mercaptoethyl) amino]-2-octanol,

2-[ 2-mercaptoethyl amino]-3-octadecan0l,

1-[ Z-mercaptoethyl) amino]-2-methyl-2-propanol, 1 -[(2-mercaptoethyl)amino]-2-methyl-2-pentanol;

and tertiary amines such as 2-[(2-mercaptoethyl)methylamino] ethanol,2[( 3 mercaptopropyl)methylamino] ethanol, 2 [nonyl(2mercaptoethyl)amino]ethanol, 2-[isopropyl(Z-mercaptoethyl)amino]ethanol, 2- [butyl(2-mercaptoethyl)amino]ethanol, and the like.

The alcohols which are monohydric and cyclic are illustrated byalicyclic mono-amines such as 2-[(2-mercaptoethyl-amino1cyclohexanol, 2[(3-mercaptoethyl)methyl amino]eyclohexanol, and4-ethyl-2-[(Z-mercaptoethyl) amino]cyclopentanol; and by heterocyclicmono-amines including an exocyclic oxygen atom such asl-(2-mercaptoethyl) -3-piperidinol, 1- 2-mercaptoethyl -4-piperidinol,1-(2-mercaptoethyl)-3-piperidinemethanol and so forth.

The class of mono-oxy mono-amines of the invention which are ethersinclude, for example and so forth.

Still another class of mono-amines provided by this invention arepoly-oxy compounds, containing more than one connective oxygen atom.

This class is inclusive, firstly, of poly-oxy compounds comprisingpolyols. Illustrative polyols of this nature, comprisingmercaptoalkylaminoalkanepolyols, include 3 (Z-mercaptoethylamino-1,2-propanediol,

3-[ (Z-mercaptoethyl) amino] -1,-2-butanediol,

2-[ (Z-merca-ptoethyl) amino] -l,3-butanediol,

3- (3 mercaptopropyl) amino] -1,2-propanediol,

3 (4-mercaptobutyl) -amino] -1,2-propanediol,

2-[ 2-mercaptoethyl) amino]-l ,4-butanediol,

2-[ B-mercaptopropyl) amino] -3-methyl-1 ,4-butanediol,

3 2-mercaptoethyl) amino] -1,2-octadecanediol,

4-[ Z-mercaptoethyl) amino] 1 ,2-cyclohexanediol,

3 (Z-mercaptoethyl)methylamino] -1,2-propanediol,

2-[ (Z-mercaptoethyl) amino] -2-(hydroxymethyl) -1,3-

propanediol,

2-[ (Z-mercaptoethyl) amino] -1,3-propanediol,

3-[ (3-mercaptopropyl) amino] -3-( 2-l1ydroxyethyl) 1,5

pentanediol,

3-[(2mercaptoethyl) amino]-1,2,4-butanetriol,

and the like.

The mono-amino poly-oxy compounds of the invention also includealkoxyalkanols such as l-[ (Z-mercaptoethyl) amino] -3-methoxy-2-propanol,

1-[ (3 -mercaptopropyl) amino] -3 -butoxy-2-propanol,

1-[ Z-rnercaptoethyl) amino] -3 -pentoxy.-2-propanol,

1- [ethyl (2-mercaptoethyl) amino] -2-cyclohexyloxy-2- propanol,

11. (Z-mercaptoethyl) amino] -4'-methyl-1-methoxy-2- pentanol, I1-[(Z-mercaptoethyl)amin'omethyl]-5-hydroxypyran, and the like; andpolyet-hers including, for example,

The diamines of the inventioninclude as a first classmono(rnercaptoalkyl-)oxyalkyl diamines which in turn includeN-mercaptoalkyl N'-oxyalkylalk-ylene diamines andN-mercaptoalkyloxyalkylenediamines of the formula where x is 1 to 3-,each R is aliphatic hydrocarbon and each R is H or aliphatic hydrocarbonas defined above.

Referring to the alkylene diamines, these includes alcohols such as3-(2-[ (Z-mercaptoethyl) amino] ethylamino -2-butanol,

3-(2- (Z-mercaptoethyl) amino] -1-methy1propylamino 2-butanol,

2- 2-[ (Z-mercaptoethyl) amino] ethylamino) cyclohexanol,

and so forth; and ethers such as 2- (2- [Z-methoxyethyl amino]-ethylamino etha nethiol, 2-(2- (3-metl1oxypropyl)amino]ethylamino)-ethanethiol, 2- 3 (Z-propoxyethyl) amino] pro pylamino ethanethiol, 2-(3-[ (4-morpholinyl propyl] amino ethanethiol,

2-[ (6-[ mct'hoxymethyl) amino] hexyl) amino] ethanethiol and so forth.The oxyalkylene diamines are illustrated by alcohols such as1-dimethylamino-3'-[ (Z-mercaptoethyl) amino] -2- prop anol,l-diethyla1nino-3-[ (Z-mercaptoethyl) amino]:-2-propanol,1-methylamino-3 2-mercaptoethyl) amino] -2-propanol, and ethers such as2-[ (3 -dimethylamino-Z-methoxypropyl) amino] ethanethiol, 2-Z-morpholinylmethylamino ethanethiol, 2-[(6-dimethylarnino-3-methoxyhexyl) amino] ethanethiol and so forth.

A further embodiment of the diamines of the invention comprisesbis(.mercaptoalkyl)oxyalkylene diamines. These include alcohols whichare monohydric such. as

The stated diamines also include, for example, alkoxyalkanols such as 12 1,4-bis[ ('2-mercaptoethyl) amino] -2-methoxy-3 -butanol, 1,4-bis (3-mercaptopropyl) amino] -2-ethoxy-3 -butanol, 1.,4-bis (Z-mercaptoethyl)amino] -3 -pentoxy-2-butanol, 1- 2-mercaptoethyl) amino] -4-(3-mercaptopropyl) amino]'-3-butoxy-2-butanol, 3 ,6-bis(2-mercaptoethyl)amino] -5-methoxy-4-octanol,

and so forth; ethers such as N,N='-bis(2'-mercaptoethyl) -3-m'ethoxy-1,6-hexanediamine,v and so forth.

Still" another class of novel compounds provided by the invention. areesters of the mercaptans of the invention, wherein a hydroxy radical, amercapto radical, or both such radicals are esterified by an acylradical of the formula RCO- where R is a saturated. aliphatichydrocarbon radical. Thus, for example, the invention includes esterssuchas 2-[ (Z-mercaptoethyl) amino] ethanol diacetate,

2-[ 3-mercaptopropyl) -amino] ethanol diacetate,

1-[ (Z-mercaptoethyl) aminol-Z-propanol diacetate,

1-[ (3-mercaptopropyl) amino] -2-butanol diacetate,

2- (Z-mercaptoethyl) amino] -4-methylcyclohexanol diacetate,

2- [isopropyl (Z-mercaptoethyl) amino] ethanol diacetate,

2'- (2-mercaptoethyl) amino] ethanol dipropionate,

3 (.2-mercaptoethyl') -amino] -1-propanol dibutyrate,

3-[(2-mercaptoethyl) aminol-Z-butanol dihexanoate,

2,- (.Z-mercaptoethyl) amino] ethanol dioctanoate,

2-[ (Z-acetoxyethyl) amino] ethanethiol,

2- (Z-acetylthioethyl) amino 1 -ethanol,

2-[ (3 -acetylthiopropyl') amino] -1-methyl-1-cyclohexanol,

and so forth.

Referring now to the preparation of the presently provided compounds,the useful. kinds of synthetic methods for producing the aminoalkanolsand aminoalkyl ethers of the invention may be regarded as including twogeneral types. The first isa ring-opening reaction, and the second is acondensation reaction.

Ring-opening reactions are adapted to introduce mercaptoalkyl andhydroxyalkyl radicals into amines to provide the compounds of theinvention. Ring opening of ethylene sulfide may be used to supply themercaptoethyl radical,- and ring opening of ethylene oxide or a likealkylene oxide, to introduce a hydroxyalkyl radical.

Thus, a convenient method for the preparation. of theZ-mercaptoethylamino compounds of the invention is the reaction ofethylene sulfide with an oxyalkylene-substituted amine. This is themethod identified in the table above as Method A. For example, thereaction of 2- aminoethanol with ethylene sulfide may be employed toproduce addition with ring opening, forming2-[(2-mercaptoethyl)amino]ethanol.,A difficulty with such a synthesis isthe fact that polar hydroxyalkyl-substituted amines tend to producepolymerization of ethylene sulfide with itself, and the ethylene sulfidepolymer may contaminate the product or indeed, constitute the major orsole product of contact of ethylene sulfide with the polar amine. Thisdifficulty can, however, be overcome by a method set forth in co-pendingapplication S.N. 176,408 and now Patent No. 3,231,617 filed by John C.James on February 28, 1962, in accordance with which N-mercaptoalkylderivatives of polar amines are prepared by contacting ethylene sulfidewith a polar amine in a mixed solvent system. In accordance with thismethod, the ethylene sulfide is introduced gradually into a reactionmixture comprising the oxyalkyl amine and a solvent mixture of a majorproportion of a solvent of low polarity such as benzene and a minorproportion of a solvent of relatively high polarity such as ethanol. Itis found that this procedure substantially obviates formation ofethylene sulfide polymer and produces satisfactory yields of the desiredZ-mercaptoethyloxyalkyl amines.

The amines which may advantageously be employed in the reaction withethylene sulfide, whether polar or not, are those containing the residueof the desired product, to which the mercaptoethyl radical need merelybe added 13 as an amine nitrogen substituent to produce the compounds ofthe invention. Thus, useful oxyalkyl amines which may be employed forreaction with ethylene sulfide to produce mereaptoalkylaminoalkanols,ethers, and the like in accordance with this invention comprise, forexample, alkanols such as Z-aminoethanol, 3-amino-1-propanol,4-amino-1-butanol, 2-amino-1-butanol, 1-amino-2-butanol,l-amino-Z-octanol, amino-tert-butanol, 1-amino-2-methyl-2-pentanol,Z-aminocyclohexanol, 2-methylaminoethanol, 2-isopropylaminoethanol,Z-piperidinol, and so forth;

alkoxyalkylamines such as Z-methoxyethylamine,

3-methoxypropylamine, 3-isopropoxypropylan1ine,1aminomethyltetrahydropyran,

and so forth; polyoxyamines such as 3-amino-1,2-propanediol,1-amino-2,3-butanediol, 1-amino-3-methoxy-2'propanol, 1-amino-3-butoxy-2-propanol, 1-amino-3 -pentoxy-2-propanol,

2- Z-methoxyethyloxy) ethylamine and oxypolyamines such as1-amino-3-dimethylamino-Z-propanol; 4- 3-aminopropyl morpholine,N-(Z-methoxyethyl)ethylenediamine, and so forth.

The products of the reaction in this case will be compounds provided bythis invention as stated above, such as 2- (Z-mercaptoethyl) amino]ethanol.

Oxyalkyl amines such as those just mentioned can also be reacted withpropylene sulfide to make the mercapto propylamino oxyalkyl compounds ofthe invention. However, this compound, unlike ethylene sulfide, mayproduce a mixture of isomers as product. Therefore, a preferred methodof making such mercaptopropylamino compounds is the condensationreaction discussed hereinafter.

Ring-opening reactions for making the compounds of this invention,besides the ethylene sulfide reaction discussed above, include ringopening of epoxyalkanes. By epoxyalkanes is meant vic-epoxy-alkanes,where the epoxy oxygen is attached to each of two adjacent carbon atoms.They may contain one or more than one such epoxy configuration.

In preparation of the compounds of this invention, such epoxides will bereacted with an alkylamine. In general, this cannot be amercaptoalkylamine, because the mercapto group is subject to attackunder the conditions empioyed to react the cyclic oxide with the amine.However, if the hydrogen attached to sulfur in a mercaptoalkyl amine isreplaced by an aralkyl radical like benzyl, the sulfur atom is blockedand protected. Debenzylation can be later effected, as discussedhereinafter, to produce the corresponding mercaptan. The steps ofreaction of an epoxide with a benzylthioalkylamine followed bydebenzylation comprise the method identified in the tables above asMethod B.

Some of the products of the staated first step of Method B and of MethodC as described hereinafter are new compounds. They are described andclaimed in copending applications S.N. 176,406 now Patent No. 3,231,612,S.N. 176,410 now Patent No. 3,197,506, and SN. 176,- 411 now Patent No.3,303,218, each filed February 28, 1962 by Robert J. Wineman, Morton H.Gollis, and John C. James.

Thus, the presently contemplated method comprises opening the ring of avic-epoxyalkane in reaction with a benzylthioalkylamine. The method canbe illustrated, for example, by reference to the reaction of propyleneoxide with a benzylthioalkylamine, as shown in the following equation:

pCI-hS-h-NH CHZCHCHQ CH2SR1NOHzCHCH R, o R1 nt where R and R are asdefined above and CH is the benzyl radical. It has been established thatthe epoxy ring opens at the least substituted carbon atom, so thatepoxides such as 1,2-epoxypropane can be employed to produce a secondaryalkanol. Polyols of the present invention can be produced, for example,by employing a diepoxyalkane such as butadiene diepoxide, or anepoxyalkano-l such as glycidol. Reaction of an epoxide as hereincontemplated can usefully be employed to produce (by way of thedebenzylation of the benzylthio compound) not only the hydroxy compoundsof this invention, but also the alkoxyalkanols, by employing an alkoxyepoxy alkane as the reactant.

Thus, useful epoxides comprise vic-epoxyalkanes such as ethylene oxide,

propylene oxide,

1,2-butylene oxide, 2,3-butylene oxide, Z-methylpropylene oxide,2-methyl-1,2-pentylene oxide, cyclohexene oxide,

butadiene diepoxide,

2,3 :4,5-diepoxyhexane,

1,2 3 ,4-diepoxy-cyclohexane,

" 2,3-epoxy-1-propanol,

3,4-epoxy-1-butanol, 2,3-epoxypropyl n-butyl ether, 2,3-epoxypropyl2-methylbutyl ether, 2,3-epoxycyclohexyl methyl ether, and so forth.

The benzylthioalkylamines with which the epoxy compounds may be reactedin making the presently provided compounds are benzylthioalkyl amineswherein alkyl is saturated aliphatic hydrocarbon, the amine nitrogenatom carries at least one hydrogen substituent, and any N substituentother than H is saturated aliphatic hydrocarbon. Thus, useful aminesinclude, for example 2- benzylthio) ethylamine,

2- benzylthio -N-methylethylamine,

2- benzylthio) -N-ethylethylamine,

2- benzylthio -N-propylethylamine,

3 -(benzy1thio) -1-propylamine, Z-(benzylthio) -1-butylamine,

2- benzylthio) -1-propylnonylamine,

3- (benzylthio -N-cyclohexyl-l-propylamine and so forth.

Products of such reaction will comprise, for example 1-( [Z-(benzylthio)ethyl] amino) -2-propanol,

1-( [2-benzylthio) ethyl] amino) -3 -methoxy-2-prop anol, 1-( [3benzylthio propyl] amino -2-propanol, 1,4-bis( [2- benzylthio )ethyl]amino) -2, 3-butanediol,

and so forth, which can be converted to corresponding mercaptans bydebenzylation as described hereinafter.

The conditions for conducting the stated ring-opening reactions mayconsist merely of contacting the cyclic compound with the otherreactant. Reaction tends to be immediate and vigorous. The temperaturemay range from above freezing to below the decomposition temperature ofthe reaction mixture components, broadly; more particularly, holding thereaction temperature at 50100 C. is favorable. The reaction may beexothermic, and dropwise addition of the cyclic compound to the reactionmixture is usually preferable.

Generally, not more than about one equivalent of the cyclic compoundwill be introducedper equivalent of amine, where one equivalent is onemole divided by the number ofreactive amine groups and of epoxy groups,respectively; and less may be used, where incomplete conversion isacceptable. Solvents and diluents are desirable, and useful solvents anddiluents include, for example,

hydrocarbons such as benzene and hexane; ethers such as diethyl etherand dioxane; alcohols such as methanol and ethanol, and so forth. Theuse of a rnixedsolvent system for reaction of ethylene sulfide withpolar amines has been mentioned above. Maintaining an atmosphere ofnitrogen over the reaction mixture is useful in preventing access ofair, Atmospheric pressures are suitable, though variation of pressureabove and below atmospheric may be employed if desired.

Referring now to the above-mentioned condensation reaction employed toprepare the present compounds, this is a condensation. of a benzyl.haloalkyl sulfide with an amino-substituted oxyalkyl compound having atleast one free amine hydrogen substituent. The condensation releaseshydrogen halide to produce a benzylthioalkylamino oxyalkyl compoundwhich can be dehenzylated as described hereinafter to the correspondingmercaptoalkylamino oxyalkyl compound. This is Method C referred toabove. Useful benzyl haloalkyl sulfides include for example, bromides,chlorides and iodides such as benzyl 2- chloroet-hyl sulfide, benzyl3-chloropropyl sulfide, benzyl. 3-bromopropyl sulfide, benzyl3-iodobutyl sulfide, benzyl' Z-chlorobutyl sulfide, benzylZ-chloropropyl sulfide, and so forth. Useful amino oxyalkyl compoundsinclude, for example, l-amino-Z-propanol, 3-amino-l-propanol,larnino-3-butanol, l-amino-Z-butanol, l-amino- 2-methyl-2-propanol,1-amino-3-methyl- 2 butanol, l-

methylamino-3-methyl-3-butanol, 2-amino-3 hexanol, 3-

arnino-Z-methoxy-l-propanol, B-methoxy-l-propylamine,

3- hydroxymethyl -piperidine, 3 -amino-1,2,4-butanetriol,

3-amino-l,2-propanediol, 2-amino 1,3 butanediol', 2-amino-Z-(hydroxymethyl)-l,3-propanediol, 2 (methylamino)ethanol, 2(ethylarnino)ethanol, 2 (propylamino)-ethanol,Z-(ethylamino)-l-propanol, Z-(butylamino -l-butanol, 2-(2,3-dimethylbutyl amino]ethanol, 3 methylarnino-2,2-dimethyll-propanol, 3-methoxy- 1, fi-hexanediamine and so forth.

Products of the condensation of the amine with the halide willcorrespond to the mercaptans of this invention, except that a benzylthiogroup will appear in place of the mercaptan group. Thus, the productswill include, for example, amines such asN-(Z-benzylthioethyl)-3-hydroxypiperidine, N (2benzylthioethyl)-3-hydroxy-4- pipecoline, N (2benzylthioethyl)-3-methoxy-1-propylamine,2-[(3-benzylthiopropyl)amino]-ethanol and the like.

Conditions for the preparation of the compounds of the present inventionby the condensation reaction may comprise merely contacting the halidewith the amine. Their ratio maybe about that of a 1:1 equivalency,calculated on the number of reactive halogen atoms and amine radicalsthey respectively contain, or an excess of either may be used.

Acid is released by the condensation reaction, and desirably the halideand amine are contacted in the presence of a base. Useful bases aresalts containing oxygen in the anion including hydroxides such as KOH,oxides such as lime, carbonates such as sodium carbonate; tertiaryamines like triethylamine and pyridine; and so forth. The amount of baseused will generally be approximately the calculated quantity needed toneutralize acid released, but more, such as up to 5 times thetheoretical equivalent, may be used if desired.

As to the other conditions of reaction, the presence of solvents ordiluents is desirable. These preferably are polar solvents, able to.dissolve the base, such as the climethyl ether of diethylene glycol,alcohols such as ethanol, and so forth. Temperatures may range fromabove freezing to below the decomposition temperatures of react-ionmixture components; a range of l50 C. is generally suitable. Pressuremay also vary over a wide range, such as from sub-atmospheric pressuresof down to, say, 50 millimeters H g, up to superatmospheric pressures of1000 pounds per square inch or above. Generally, atmospheric pressuresare suitable. It is usually desirable, however, to maintain a nitrogenatmosphere over the surface of the reaction mixtures to avoid access ofair.

Referring now to the debenzylation of the benzylthioalkyamines producedin accordance with the above describedprocedures, this is effected byadding sodium to a stirred solution of the S-benzyl compound in liquidammonia. Alternate addition of the sodium and the S- benzyl compoundmaybe used to overcome the insolubility of the higher molecular weightS-benzyl mercaptoalkylamino alkanols in liquid ammonia. Sufficient totalsodium should be used to produce and maintain the characteristic darkblue color of a sodium-liquid ammonia solution for a measurable time,such as at least about /2 hour, after the addition is complete. Thearmmonia may then be allowed to evaporate at ambient pressure and thenfinal traces removed under reduced pressure (water pump), after whichthe reaction mixture will be acidified. The residue, to avoid oxidation,is desirably blanketed with nitrogen until acidification isaccomplished. Acidification will be desirably preceded by adding waterto the reaction mixture, to solubilize the residue, while the reactionmixture is cooled, as for example by chilling in an ice bath. The acidused to acidify the mixture may be any strong proton donor. which willform an acid salt with the amine. Desirably it will be a physiologicallyacceptable acid forming a physiologically acceptable addition salt withthe amine, adapted, for example, for use in physiological applicationssuch as administration of parenteral injections to animals. Usefulacids, including physiologically acceptable acids, for forming saltswithamines are known in the art. Thus for example, such useful acids includeinorganic acids such as hydrochloric, sulfamic, phosphoric and nitricacids, and organic acids such as maleic, fumaric, succinic,methanesulfonic, tartaric, citric, gluconic, itaconic andp-toluenesulfonic acids. Depending on the intended use of the product,indeed a toxic acid, such as picric, picrolonic or oxalic acid, may beused if desired. To

form the addition salt, sufficient acid will be added to provide onemole for each mole of amine groups in the product, the amount necessaryfor this depending on Whether the product is a monoamine or a polyamine.Excess acid may be used. The acidic mixture may now .be extracted with asolvent such as ether for the removal of organic byproducts. The acidicaqueous portion is a solution of the acid salt of the organic aminemixed with inorganic salt, such as sodium chloride. The organic aminesalt may be separated by evaporating the aqueous acid solution. underreduced pressure to dryness, and then extracting the residue. with asolvent such as an alcohol for the organic amine. salt. Suitablesolvents include methanol, ethanol and isopropyl alcohol. Concentrationof the extract separates the inorganic salts as a precipitate which. canbe removed by filtration, whereupon the solvent can be removed from thefiltrate to yield the amine hydrochloride.

Generally, isolation of the amine as a salt such as the hydrochloridevsalt is desirable. However, if desired,

the amine itself may be recovered from the debenzylation reactionmixture or may be produced by treatment of the hydrochloride salt, madeas described above, with alkali, such as NaOH, thus freeing the amine.In general, though, the acid addition salts of these amines are thedesirable. form thereof; because of their water solubility, they arebetter adapted than the free amine for use in physiological applicationssuch as administration of parenteral injections to animals. For such.use, the addition salts selected will be non-toxic salts such as thehydrochloride, maleate or the like. Practically any protonic acid can beused to form the acid addition salt, and useful acids, includingphysiologically acceptable acids, for forming salts with amines areknown in the art.

Referring now to the further embodiment of this invention comprisingesters of the above-discussed mercaptoalkylamines, the amines aredesirably employed to make the esters in the form of the stated salts.Usual means of esterification will be employed, such as reaction of theanhydride or acid halide of the selected acid with the amine. Thus forexample, useful acyl halides include acetyl chloride, propionylchloride, butyryl chloride, caproyl chloride, capryl chloride, and soforth. Useful anhydrides include for example acetic anhydride, propionicanhydride, butyric anhydride, valeric anhydride, enanthic anhydride.caprylic anhydride and so forth. In general, the acid derivative and theamine will be contacted in the calculated theoretical amounts,approximately. The formation of the ester by reaction of the acid halideor anhydride with the amine may or may not require heating, butgenerally proceeds rapidly at temperatures below about 100 C.

The various mercaptoalkylamines, esters and their addition saltsprovided by this invention range from mobile liquids to crystallinesolids. The acid addition salts range from moderately to very soluble inlower alkanols such as methyl, ethyl and isopropyl alcohol; they arevery soluble in water, and many of them are quite hygroscopic. They areuseful for a wide variety of industrial, pharmaceutical and agriculturalapplications. They have demonstrated activity in protectingmicroorganisms and mammals against the harmful effects of ionizingradiation. The oxyalkyl portion of the molecules of these compoundsfavorably changes their solubility and biological transmission ascompared to non-oxygenated mercaptoalkylamines such as cysteamine.Administration of the present compounds may be effected by usualpharmaceutical methods. For example, simply dissolving the amine saltsin water gives a pharmaceutically acceptable solution adapted forparenteral administration by injection. Effective dosage levelsgenerally range from 350 to 500 mg. per kg. body weight, calculated inweight of free amine. The amines may if desired be combined with othermaterials such as copper compounds to achieve additional pharmaceuticaland medicinal effects; they may be administered orally, as for examplein the form of gelatin capsules; and other variations within the usualskill of the pharmaceutical art may be made.

Additional uses for these compounds include application as chelatingagents, as for example to prevent metal ions from precipitating fromsolution; the compounds containing each of the SH, OH and NHconfigurations are especially valuable in this connection. Further, theymay be used as chemical intermediates, for example by ring closureproduced upon treatment with condensing agents such as phosphoruspentoxide, potassium bisulfate, sulfuric acid, aluminum oxide, and thelike, to prepare morpholines and thiamorpholines useful, for example, inthe preparation of dyes and of pharmaceuticals. The ethers are useful inthis connection in providing a non-reactive oxyalkyl group favoringreaction of the mercaptan radical. The tertiary amines are adapted forquaternization to provide bactericidal and detergent products. Oxyalkylcompounds of the invention including higher alkyl radicals, such as thehydrochloride salt of 2 ([3 (1 nbutylheptyloxy)propyl]amino)ethanethiol, can be used as such as surfaceactive agents; the stated compound, which has anomalously low Water andhigh organic solvent solubility, is an unusually effective emulsifyingagent. The mercapto and acylthiol functions of these compounds adaptthem for use in rubber chemicals, as for example as vulcanizing andcuring agents. The various products of the invention can also beemployed as agricultural toxicants, to rid soil and plant stands ofundesirable vegetation, nematodes, insects and the like.

While the invention has been described with particular reference tovarious specific embodiments thereof, it is to be appreciated thatmodifications and variations can be made without departing from thescope of the invention, which is limited only as defined in the appendedclaims.

What is claimed is:

1. Compounds selected from the class consisting of mercaptoalkyloxyalkyl diamines of the formula where each R is saturated aliphatichydrocarbon, each R is selected from the class consisting of hydrogenand saturated aliphatic hydrocarbon, and x is an integer of from 1 to 3,at least one of the oxy O and amino N atoms is exocyclic, and N isseparated from other hetero atoms by at least two carbon atoms; and acidaddition salts of said amines with protonic acids; wherein each of saidsaturated aliphatic hydrocarbon radicals contains up to 18 carbon atoms.2. Compounds selected from the class consisting of1,4-bis[(Z-mercaptoethyl)amino]-2,3-butanediol; and its acid additionsalts with protonic acids.

References Cited UNITED STATES PATENTS 3,165,451 8/1962 Louthan 26Q583 XCHARLES B. PARKER, Primary Examiner. R. L. RAYMOND, Assistant Examiner,

1. COMPOUNDS SELECTED FROM THE CLASS CONSISTING OF MERCAPTOALKYLOXYALKYL DIAMINES OF THE FORMULA (H-S-R1-N(-R1''))2-R2-(O-R2'')X WHEREEACH R IS SATURATED ALIPHATIC HYDROCARBON, EACH R'' IS SELECTED FROM THECLASS CONSISTING OF HYDROGEN AND SATURATED ALIPHATIC HYDROCARBON, AND XIS AN INTEGER OF FROM 1 TO 3, AT LEAST ONE OF THE OXY O AND AMINO NATOMS IS EXOCYCLIC, AND N IS SEPARATED FROM OTHER HETERO ATOMS BY ATLEAST TWO CARBON ATOMS; AND ACID ADDITION SALTS OF SAID AMINES WITHPROTONIC ACIDS; WHEREIN EACH OF SAID SATURATED ALIPHATIC HYDROCARBONRADICALS CONTAINS UP TO 18 CARBON ATOMS.